tbuckley/cabot-search huggingface dataset:
ILC2s—Bipartisan politicians in cancer
Authors: Abderezak Zebboudj, Masataka Amisaki, Vinod P. Balachandran
Journal: Science Immunology (2022)

Group 2 innate lymphoid cells (ILC2s) are lymphocytes that both promote and suppress antitumor immunity. Jou and colleagues now report in colorectal tumorigenesis that the cytokine interleukin-25 activates ILC2s to induce myeloid cells that suppress antitumor immunity.
Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC.
Authors: Fan Xu, Qingshan Li, Wenxin LI, Shenglin Zhang, Yaping Zhao, Didi Guo, Zhongyu Lu, Siqi Chen, Guanghua Lu, Fanfeng Bu, Ran Ding, Wanglong Deng
Journal: Journal of Clinical Oncology (2022)

8546 Background: Activating mutations in the ERBB2 gene were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations have emerged as therapeutic targets in non-small cell lung cancers (NSCLC). However, Activating ERBB2 mutations have not been described in detail like other driver gene mutations, such as epidermal growth factor receptor (EGFR)-activating mutations. Methods: In this study, we retrospectively analyzed activating ERBB2 mutations using next-generation sequencing(NGS). From May 2019 to January 2022, 21745 patients who were diagnosed with NSCLC were detected. Results: A total of 686 activating ERBB2 mutations were found, and 12 patients carried double ERBB2-activating mutations. In this cohort, the average age of patients was 58 years (range, 13-90 years). 59.6% of the patients were female and 88.2% were diagnosed with lung adenocarcinoma.A total of 47 ERBB2-activating mutation subtypes were defined in 674 patients. The most common activating mutations were Y772_A775dup (55.0%, 371/674), followed by G776delinsVC (8.3%, 56/674), S310F (7.7%, 52/674), G778_P780dup (5.6%, 38/674) and V659E (4.1%, 28/674). All other mutations occurred in 14 or fewer patients. ERBB2-activating mutations occurred most frequently in the tyrosine kinase domain（TKD） (80.1%), which included mutations in exon 20 (76.2%), exon 19 (3.0%), and exon 21 (1.2%),In addition, 13.2% of activating ERBB2 mutations occur in the extracellular domain, and 5.5% in the Transmembrane domain. 23.1%(156/674) patients with ERBB2 activating mutations could be evaluated for concurrent mutations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Among these patients, ERBB2-activating mutations were most frequently co-mutated with TP53(54/156) and EGFR(21/156). The frequency of EGFR mutations was much higher in non-TKD mutation patients than in TKD mutation patients (56.7% vs. 3.2%, P &lt; 0.001), but no difference was observed for TP53. All these patients were microsatellite stable (MSS) and low TMB ( &lt; 10 mutations/megabase). Conclusions: We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.
The efficacy of preoperative ureteral stenting in ureteral calculi coexisting with ipsilateral renal calculi for retrograde intrarenal surgery: Compared to percutaneous nephrostomy
Authors: Y.U. Kim, J.G. Ha, J.Y. Choi, Y.H. Ko, P.H. Song, K.H. Moon, H.C. Jung
Journal: European Urology (2022)
ATRT-26. The PI3k inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors
Authors: Tyler Findlay, Kristen Malebranche, Eric Raabe, Charles Eberhart, Jeffrey Rubens
Journal: Neuro-Oncology (2022)

Abstract We previously identified high activation of mTORC1 and mTORC2 in AT/RT by immunohistochemistry of 18 primary tumors expanding over each molecular subgroup of AT/RT. Paxalisib is a highly brain-penetrant PI3k inhibitor acting upstream of mTORC1/2 to fully inhibit the activation of both complexes. Ongoing pediatric clinical trials have reported Paxalisib as safe and well-tolerated. We find that Paxalisib leads to minimal toxicities in mice bearing AT/RT orthotopic xenografts, slows tumor growth (as determined by bioluminescent imaging), and significantly extends survival (CHLA-06: 40 to 54 days, p=0.0011; BT12: 21 to 35 days, p=0.02). However, due to limited durability of single agent therapy, we conducted pilot studies to identify rational combination therapies to further enhance these survival benefits. RG2833 is a novel, highly brain penetrant, histone deacetylase 1/3 (HDAC1/3) inhibitor. HDAC inhibitors have previously been identified as synergistic partners with PI3k/mTOR inhibitors through complementary activation of FOXO signaling pathways. We hypothesized that RG2833 would synergize with Paxalisib, minimize toxicities compared with pan-HDAC inhibitors, and maximize therapeutic benefits due to superior CNS penetration. We demonstrate that Paxalisib and RG2833 combine synergistically to decrease AT/RT cell growth (SynergyFinder ZIP score 11.1; CellTiter-Blue Cell Viability Assay, p&amp;lt;0.0001), and increase apoptosis (Western blot cPARP, MUSE Annexin V Assay, ANOVA p&amp;lt;0.001) compared to each agent alone and DMSO control. Our pilot combination study in orthotopic xenograft models of AT/RT demonstrate that combination therapy is well tolerated and slows tumor growth more significantly than each agent alone and vehicle control (IVIS bioluminescent imaging). This novel combination therapy could readily translate into a new clinical trial aimed at improving survival in this deadly pediatric brain tumor.
Changes in pituitary–gonadal hormones after enzalutamide or abiraterone plus prednisone in men with castration-resistant prostate cancer (HEAT): Results from a randomised clinical trial
Authors: K. Kvorning Ternov, J. Sønksen, M. Fode, H. Lindberg, C. Kistorp, R. Bisbjerg, J. Faber, G. Palapattu, P.B. Østergren
Journal: European Urology (2022)
LGG-18. Inhibition of Bcl-xL targets the senescent compartment of pilocytic astrocytoma
Authors: Florian Selt, Romain Sigaud, Gintvile Valinciute, Philipp Sievers, Julia Zaman, Clara Alcon, Heike Peterziel, Jessica W Tsai, Romain Guiho, Juan Pedro Martínez-Barbera, Stefan Pusch, Martin U Schuhmann, Ahmed El Damaty, Pratiti Bandopadhayay, Andreas von Deimling, Stefan M Pfister, Joan Montero, David Capper, Christel Herold-Mende, Ina Oehme, Felix Sahm, David T W Jones, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Pilocytic astrocytoma (PA) is a mitogen-activated protein kinase (MAPK)-driven disease. Treatment of sub-totally resected PA remains challenging and relapses occur even after MAPK-targeted therapies such as MEK inhibition. Oncogenic activation of the MAPK-pathway drives the majority of cells into oncogene-induced senescence (OIS). OIS might represent a complementary vulnerability exploitable by senolytic agents. Here we investigated the senolytic properties of BH3-mimetics in PA. METHODS: Four patient-derived PA cell lines, DKFZ-BT66, -BT308, -BT317 (KIAA1549:BRAF-fusion) and DKFZ-BT314 (BRAF V600E-mutation) were treated with different BH3-mimetics, chemotherapeutics and MEK-inhibitors in proliferation (expression of SV40 large T (TAg)) and OIS (repression of TAg) states. Inhibition of metabolic activity (CellTiterGlo® 2.0) and reduction of viability (trypan blue) was assessed after 72 hours. Target expression was determined using gene expression data and Western blot. On-target activity was verified by immunoprecipitation. Dependence on Bcl-xL was investigated by shRNA-mediated knockdown and BH3-profiling. Gene expression data of primary PA and 751 cancer cell lines (GDSC dataset) was analyzed. RESULTS: BH3-mimetics inhibiting Bcl-xL (Bcl-xLi; Navitoclax, A-1131852, A-1155463, AZD4320) showed activity in 3/4 models (DKFZ-BT66, -BT314 and -BT317) in the OIS state (IC50s &amp;lt;300nM). Other BH3-mimetics, chemotherapeutics and MEK-inhibitors had no effect on all models in OIS. Bcl-xL mRNA expression levels were similar, on-target activity and dependence on Bcl-xL protein was comparable in all models. Bcl-xLi-resistance of DKFZ-BT308 was linked to upregulation of genes of the HALLMARK_XENOBIOTICS_METABOLISM gene set involved in drug metabolism. Correlation of these genes with IC50s of navitoclax was validated in an independent dataset (GDSC). CONCLUSION: Treatment with Bcl-xLi is a promising strategy targeting the senescent part of PA. IC50s of the clinically available drug navitoclax were &amp;gt;20-fold below achievable plasma concentration indicating translatability. Genes from the gene set HALLMARK_XENOBIOTICS_METABOLISM could represent a predictive biomarker.
Readmission risk identification: Implementation of a patient-centered interview.
Authors: Raquel E. Reinbolt, Taylor Moline, Julie Rader, Rhonda Nilsson, Doris Garnett, Nicole Liebner, Lisa Graham
Journal: Journal of Clinical Oncology (2022)

6564 Background: Unplanned 30-day readmissions in the cancer population are common. There are few large studies describing cancer patients’ readmission perspective. To better define predisposing factors associated with readmission, our Nurse Case Manager team implemented a patient-focused survey. Methods: Cancer patients readmitted to The James Cancer Hospital from May 2020-December 2021 were included. Readmission events were defined as an inpatient hospital readmission within 30 days of the patient’s prior hospitalization. Team members conducted a 16-question survey immediately following readmission to evaluate the patients’ perspective on factors that may have contributed to their readmission; results were recorded. Results: A total of 3,333 readmissions were unplanned, 109 planned, 22 listed as other; 3,464 patients completed interviews (Table). During their index admission, most patients reported receiving (90%) and understanding (89%) discharge education/instructions. Upon index discharge, most patients (62%) were discharged on a new medication; the majority reported filling their prescription (95%) and taking it as instructed (98%). Nearly all patients had a post-index hospitalization follow up appointment scheduled, but only 58% reported attending. The primary reason reported for not attending was readmission prior to the appointment. Just over 50% of patients received a post-index hospital stay phone call. Some patients (6% yes; 58% unanswered) felt services at discharge would have been helpful. Most patients (51%) contacted their provider regarding worrisome symptoms experienced prior to being readmitted. Pain (18%), fever (11%), and shortness of breath (10%) were the most commonly reported symptoms that prompted returning to the hospital. Conclusions: To our knowledge, this is the largest study to date of cancer patients’ own perspective of their 30-day readmission. More immediate post-hospitalization follow up and increased deployment of tailored discharge services represent areas of opportunity identified to decrease readmission rates. Symptom-specific interventions may also be impactful. Due to the negative downstream effects readmissions have on the healthcare system, it is critical to develop risk mitigation strategies incorporating patient-reported experience. [Table: see text]
Role of pre-operative ureteral stent on outcomes of Retrograde Intra Renal Surgery (RIRS): Systematic review and meta-analysis of 3219 patients and comparison of Asian and non-Asian cohorts
Authors: Y.X.T. Law, J.Y.C Teoh, D. Castellani, E.J. Lim, E.O.T Chan, M. Wroclawski, G.M. Pirola, C. Giulioni, E. Rubilotta, M. Gubbioti, S. Scarcella, B.H. Chew, O. Traxer, B.K. Somani, V. Gauhar
Journal: European Urology (2022)
HGG-02. Epigenetic transcription regulation and 3D genome structure in pediatric high-grade glioma
Authors: Tina Huang, Juan Wang, Ye Hu, Andrea Piunti, Elizabeth Bartom, Ali Shilatifard, Feng Yue, Amanda Saratsis
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are highly morbid brain tumors. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding Histone H3. To investigate whether the H3K27M mutant protein is associated with distinct chromatin structure affecting transcription regulation, we generated the first high-resolution Hi-C and ATAC-Seq maps of pHGG cell lines, and integrated these with tissue and cell genomic data. METHODS: We generated sequencing data from patient-derived cell lines (DIPG n=6, GBM n=3, normal n=2) and frozen tissue specimens (DIPG n=1, normal brainstem n=1). Analyses included cell line RNA-Seq, ChIP-Seq (H3K27ac, H3K27me3, H3K27M) and genome-wide chromatin conformation capture (Hi-C), as well as tissue ATAC-Seq. Publicly available pediatric glioma tissue ChIP-Seq data was integrated with cell data. CRISPR knock-down of target enhancer regions was performed. RESULTS: We identified tumor-specific enhancers and regulatory networks for known oncogenes in DIPG and GBM. In DIPG, FOX, SOX, STAT and SMAD families were among top H3K27Ac enriched motifs. Significant differences in Topologically Associating Domains (TADs) and DNA looping were observed at OLIG2 and MYCN in H3K27M mutant DIPG, relative to wild-type GBM and normal cells. Pharmacologic treatment targeting H3K27Ac (BET and Bromodomain inhibition) altered these 3D structures. Functional analysis of differentially enriched enhancers in DIPG implicated SOX2, SUZ12, and TRIM24 as top activated upstream regulators. Distinct genomic structural variations leading to enhancer hijacking and gene co-amplification were identified at A2M, JAG2, and FLRT1. CONCLUSION: We show genome structural variations enhancer-promoter interactions that impact gene expression in pHGG in the presence and absence of the H3K27M mutation. Our results imply that tridimensional genome alterations may play a critical role in the pHGG epigenetic landscape and thereby contribute to pediatric gliomagenesis. Further studies examining the impact of the alterations are therefore underway.
MR-guided adaptive versus CT-guided stereotactic radiotherapy for prostate cancer: Where is the best cost-benefit balance?
Authors: A. Castelluccia, D. Marchesano, G. Grimaldi, I. Annessi, F. Bianciardi, A. Di Palma, M. Valentino, L. Verna, V. Confaloni, F. Rea, B. Tolu, C. Borrazzo, M. Rago, M. Masi, R. El Gawhary, P.C. Gentile
Journal: European Urology (2022)
Walras, a novel lncRNA linked to cardiomyocyte cytoarchitecture and atrial fibrillation
Authors: D Franco, J Dominguez, V Lodde, R Munk, K Abdelmohsen, M Gorospe, V Jimenez-Sabado, A Ginel, L Hove-Madsen, A Aranega, C Garcia-Padilla
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Junta de Andalucia Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in humans. Genetic and genomic analyses have recently demonstrated that the homeobox transcription factor Pitx2 plays a fundamental role regulating expression of distinct growth factors, microRNAs and ion channels leading to morphological and molecular alterations that promote the onset of AF. Here we address the plausible contribution of long non-coding (lnc)RNAs within the Pitx2&amp;gt;Wnt&amp;gt;miRNA signaling pathway. In silico analyses of annotated lncRNAs in the vicinity of the Pitx2, Wnt8 and Wnt11 chromosomal loci identified five novel lncRNAs with differential expression during cardiac development. Importantly, three of them, Walaa, Walras and Wallrd, are evolutionarily conserved in humans and displayed preferential atrial expression during embryogenesis. In addition, Walrad displayed moderate expression during embryogenesis but was more abundant in the right atrium. Walaa, Walras and Wallrd were distinctly regulated by Pitx2, Wnt8, and Wnt11, and Wallrd was severely elevated in conditional atrium-specific Pitx2-deficient mice. Furthermore, pro-arrhythmogenic and pro-hypertrophic substrate administration to primary cardiomyocyte cell cultures consistently modulate expression of these lncRNAs, supporting distinct modulatory roles of the AF cardiovascular risk factors in the regulation of these lncRNAs. Walras affinity pulldown assays revealed its association with distinct cytoplasmic and nuclear proteins previously involved in cardiac pathophysiology, while loss-of-function assays further support a pivotal role of this lncRNA in cytoskeletal organization. We propose that lncRNAs Walaa, Walras and Wallrd, distinctly regulated by Pitx2&amp;gt;Wnt&amp;gt;miRNA signaling and pro-arrhythmogenic and pro-hypertrophic factors, are implicated in atrial arrhythmogenesis, and Walras additionally in cardiomyocyte cytoarchitecture.
Seizure- or Epilepsy-Related Emergency Department Visits Before and During the COVID-19 Pandemic — United States, 2019–2021
Authors: Sanjeeb Sapkota, Elise Caruso, Rosemarie Kobau, Lakshmi Radhakrishnan, Barbara Jobst, Jourdan DeVies, Niu Tian, R. Edward Hogan, Matthew M. Zack, Daniel M. Pastula
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Abbreviation: ED = emergency department.* The y-axis range differs for different age groups to account for different numbers of ED visits by these groups and to facilitate visualization of changes over time.† The National Syndromic Surveillance Program receives deidentified medical record information from approximately 71% of nonfederal EDs nationwide.To reduce artifactual impact from changes in reporting patterns, analyses were restricted to facilities with more consistent reporting of more complete data (coefficient of variation ≤40 and average weekly informative discharge diagnosis ≥75% complete during 2019-2021).
Molecular characteristics of <i>EGFR</i> exon20 mutations in NSCLC patients.
Authors: Yinghua Ji, Jin Wang, Xiangli Meng, Jinling Xie, Ping Lu, Mengmeng Li, Ningning Luo, Yingxue Qi, Xiaofeng Zhu
Journal: Journal of Clinical Oncology (2022)

e21011 Background: EGFR exon 20 mutations are associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 mutations are usually not present alone, suggesting a more complex subtype of exon 20 mutations. Methods: In this study, we retrospectively analyzed the different subtypes and compound mutation profiles of EGFR 20 mutations. A total of 1,233 NSCLC patients’ tumors were collected and the mutations were detected by next-generation sequencing (NGS) from May 2020 to June 2021. Results: A total of 415 NSCLC patients' tumors harbored EGFR exon 20 mutations, accounting for 33.66% of the entire EGFR mutation cohort. Among these 415 patients, most of mutations were single-nucleotide variant (SNV) (379; 91.33%), and a few were indel or insertion mutations (39; 9.40%). The insertions were all in the back of exon 20, which were resistant to EGFR-TKIs. In addition, the subtypes of SNV were concentrated in T790M (270; 71.24%), S768I (48; 12.66%) and C797S (33; 8.71%), and all T790M mutations were accompanied by other mutations. Notably, the compound mutations of exon 20 have also been analyzed in this study. EGFR exon 20 combined with other EGFR mutations were detected in 345 patients. The compound mutations of exon 20-18, exon 20-19, exon 20-20 and exon 20-21 were detected in tumors from 52 (15.07%), 163 (47.25%), 43 (12.46%) and 140 (40.58%) patients respectively. Remarkably, the compound mutation subtype of exon 20-20 was T790M/C797X (29; 67.55%) and exon 20-21 was T790M/L858R (124; 88.57%). Conclusions: Diverse patterns of SNV mutations are seen in EGFR exon 20 mutations tumors. EGFR 20 mutations often accompany other mutations, which are associated with resistance to EGFR-TKIs. These data may help avoid the resistance of future adjuvant targeted therapy.
Associations between diet quality and chronic health conditions (CHCs) in adult survivors of childhood cancer in the St. Jude Lifetime Cohort Study (SJLIFE).
Authors: Emily R Finch, Elizabeth Foley, Geehong Hyun, Chelsea Goodliffe Goodenough, Fang Fang Zhang, Kevin R. Krull, Nickhill Bhakta, Yikyung Park, Matthew J. Ehrhardt, Tara M. Brinkman, Jennifer Q. Lanctot, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2022)

12095 Background: Survivors of childhood cancer are at increased risk for early development of CHCs, including metabolic syndrome (MetS), low bone mineral density (LBMD), and gastrointestinal (GI) disease. Dietary modification is often recommended for prevention and/or treatment of these CHCs in non-cancer populations. However, associations between diet quality and severity of CHCs in adult survivors of childhood cancer are not well known. Methods: Adult survivors (≥10 years post-diagnosis) of childhood cancer who completed a clinical evaluation and Block Food Frequency Questionnaire were included. Diet quality was estimated using the Mediterranean diet score (aMED), with scores ranging from 0 to 9 (increased scores represent higher adherence to diet). CHCs were graded (modified CTCAE) and classified as “low” (grade ≤1 for LBMD and GI; grade ≤2 for MetS) or “high” (grade 2-4 for LBMD and GI; grade 3-4 for MetS). A multivariable linear regression model was used to estimate the mean aMED score by “low” or “high” disease category, with adjustment for age at evaluation, sex, race, education, total energy intake, adjusted BMI, physical activity, smoking, and alcohol consumption. Results: 2,822 survivors of childhood cancer (52.4% male, 83.1% non-Hispanic white) were included. The most prevalent diagnosis was acute lymphoblastic leukemia (34.1%). Time from primary diagnosis was 24.2±8.5 years and age at recruitment was 32.5±8.7 years. Lower adherence to aMED diet was associated with “high” MetS and LBMD, but not GI disease. See the Table for aMED multivariate-adjusted diet quality scores by CHC. Conclusions: In this cross-sectional analysis, MetS and LBMD were associated with poor adherence to the aMED diet. Although longitudinal investigation of associations between diet quality and CHCs in survivors of childhood cancer are needed to determine causal association between diet quality and CHCs in childhood cancer survivors, dietary interventions in early or late cancer survivors may help prevent development or progression of specific treatment related chronic conditions. [Table: see text]